IL36RN – Generalized pustular psoriasis

Generalized pustular psoriasis (GPP) is a severe, potentially life-threatening autoinflammatory skin disorder characterized by recurrent sterile neutrophilic pustules on erythematous skin and systemic manifestations such as fever and leukocytosis. Mutations in IL36RN, encoding the interleukin-36 receptor antagonist (IL-36Ra), were first implicated by exome sequencing in five unrelated GPP patients, identifying biallelic loss-of-function alleles as a Mendelian cause of recessive GPP (PMID:21839423).

Genetic studies across diverse populations have confirmed a robust autosomal recessive association. In a Japanese cohort, 9 of 11 GPP patients without psoriasis vulgaris and 2 of 20 with preceding vulgaris harbored homozygous or compound heterozygous IL36RN mutations (PMID:23698098). Case series report additional probands spanning infancy to nonagenarians, with a broad variant spectrum including missense (e.g., c.368C>T (p.Thr123Met)), nonsense (e.g., c.28C>T (p.Arg10Ter)), splice-site (e.g., c.115+6T>C), and frameshift alleles.

Segregation of biallelic IL36RN variants with GPP has been demonstrated in multiple multiplex families. Homozygosity mapping in nine Tunisian pedigrees and compound heterozygous segregation in a Japanese ACH sib-pair (p.Ser113Leu) provide confirmatory evidence for recessive inheritance, with at least one additional affected relative documented in these families.

Functional assays support haploinsufficiency as the pathogenic mechanism. The p.Leu27Pro substitution (c.80T>C) impairs IL-36Ra stability and secretion and fails to antagonize IL-36-induced NF-κB activation in keratinocyte reporter assays, leading to unrestrained IL-8 production (PMID:21848462). Structural modeling corroborates disruption of receptor binding.

Some IL36RN alleles, such as p.Pro82Leu, show normal mRNA and protein expression in patient keratinocytes and lack functional impairment, indicating genotype-phenotype nuances and the need for careful variant interpretation (PMID:37525499).

Integration of genetic and experimental data establishes IL36RN deficiency (DITRA) as a definitive cause of recessive GPP. Genetic testing enables early diagnosis, informs prognosis, and guides emerging therapies targeting IL-36 signaling. Key take-home: Biallelic IL36RN mutations underlie DITRA, supporting IL-36 blockade in refractory GPP.

References

• American Journal of Human Genetics • 2011 • Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. PMID:21839423
• The Journal of Investigative Dermatology • 2013 • The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist. PMID:23698098
• The New England Journal of Medicine • 2011 • Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. PMID:21848462
• The Journal of Dermatology • 2023 • Expression of interleukin-36 receptor antagonist in a patient with generalized pustular psoriasis harboring the p.Pro82Leu variant in the IL36RN gene. PMID:37525499

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